Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC CURAMUS, Hôpital Saint-Antoine, Service d'Hématologie Biologique, 75012, Paris.
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Service d'Hématologie Clinique et de Thérapie Cellulaire, 75012, Paris.
Haematologica. 2023 Jan 1;108(1):61-68. doi: 10.3324/haematol.2022.280676.
Chemotherapy resistance is the main cause of treatment failure in acute myeloid leukemia (AML) and has been related to ATP-binding cassette (ABC) transporter activity. However, the links between ABC activity, immunophenotype, and molecular AML parameters have been poorly evaluated. Moreover, the prognostic value of ABC activity, when compared to new molecular markers, is unknown. Here we investigated the links between ABC activity, as evaluated by JC-1 +/- cyclosporine A assay, and immunophenotypic, cytogenetic, molecular, and targeted next-generation sequencing features in 361 AML patients. High ABC activity was found in 164 patients and was significantly associated with less proliferating disease, an immature immunophenotype (expression of CD34, HLA-DR, CD117, CD13), and gene mutations defining AML as belonging to secondary-type ontogenic groups. Low ABC activity was associated with more mature myeloid differentiation (CD34-, cyMPO+, CD15+, CD33+) or monocytic commitment (CD64+, CD4+weak, CD14+), with NPM1 mutations, KMT2A rearrangements, and core-binding factor gene fusions, hallmarks of the de novo-type AML ontogeny. ABC activity was one of the major factors we identified using a random forest model for early prediction of AML ontogeny. In the 230 patients evaluated at diagnosis and intensively treated, high ABC activity was a predictive factor for primary resistance, and in multivariate analysis including full molecular data, an independent factor for event-free survival (P=0.0370). JC-1 +/- cyclosporine A assay could be used at diagnosis to predict AML ontogeny and to complete prognosis evaluation in addition to new molecular markers.
化疗耐药是急性髓细胞白血病（AML）治疗失败的主要原因，与三磷酸腺苷结合盒（ABC）转运体活性有关。然而，ABC 活性、免疫表型和分子 AML 参数之间的联系尚未得到充分评估。此外，与新的分子标志物相比，ABC 活性的预后价值尚不清楚。在这里，我们研究了 361 例 AML 患者中 ABC 活性（通过 JC-1 +/-环孢菌素 A 测定评估）与免疫表型、细胞遗传学、分子和靶向下一代测序特征之间的关系。在 164 例患者中发现 ABC 活性较高，与疾病增殖较少、不成熟的免疫表型（CD34、HLA-DR、CD117、CD13 表达）和定义 AML 属于继发性起源组的基因突变显著相关。低 ABC 活性与更成熟的髓样分化（CD34-、cyMPO+、CD15+、CD33+）或单核细胞分化（CD64+、CD4+弱、CD14+）相关，与 NPM1 突变、KMT2A 重排和核心结合因子基因融合相关，这些都是 AML 新发生型起源的标志。ABC 活性是我们使用随机森林模型对 AML 起源进行早期预测时确定的主要因素之一。在 230 例接受诊断和强化治疗的患者中，高 ABC 活性是原发性耐药的预测因素，在包括全分子数据的多变量分析中，是无事件生存的独立因素（P=0.0370）。JC-1 +/-环孢菌素 A 测定可在诊断时用于预测 AML 起源，并在新的分子标志物之外完成预后评估。
